Farrerol ameliorated renal fibrosis mediated by mitophagy deficiency in cisplatin-induced chronic kidney disease via Nrf2/PINK1

Background: and Purpose: Mitochondrial dysfunction is essential in renal tubular damage, and mitophagy, a selective form of autophagy, specifically eliminates damaged mitochondria. Mitophagy reportedly protects against diabetic kidney disease, cisplatin-induced acute kidney injury (AKI) and other related kidney diseases, but the specific mechanism by which mitophagy protects against cisplatin-induced chronic kidney disease (CKD) remains unclear. Experimental Approach: The effects of farrerol on cisplatin-induced AKI in mice were investigated. C57BL/6 wild-type and Nrf2 knockout mice were used to evaluate the protective effect of farrerol on cisplatin-induced CKD. Key Results: we confirmed that Nrf2- and PINK1/Parkin-mediated mitophagy was significantly increased on the 3rd day of cisplatin stimulation but was reduced on the 38th day of cisplatin stimulation. Similar to previous results, farrerol, a natural compound, also activated Nrf2 on the 38th day of cisplatin administration, subsequently stimulating the Nrf2-targeted antioxidant enzymes HO-1 and NQO1. In addition, farrerol triggered PINK1/Parkin-mediated mitophagy by recruiting the receptor proteins LC3 and p62/SQSTM1, thereby eliminating damaged mitochondria. Furthermore, genetic deletion of Nrf2 reduced PINK1/Parkin-mediated mitophagy activation and led to increased renal tubular necrosis and renal fibrosis. We also found that farrerol alleviated inflammation and renal fibrosis by inhibiting p-NF-κB/NLRP3 and TGF-β/Smad signaling. Conclusions: These data indicated that farrerol effectively inhibited cisplatin-induced inflammation and renal fibrosis by activating Nrf2 and PINK1/Parkin-mediated mitophagy, which provides a potential novel therapeutic target for CKD.